Compound effective as cerebral insufficiency improver

ABSTRACT

A compound having the formula (I): ##STR1## wherein A is --CH 2  --, --O--, or --S--; R 1  is CH 3  or OCH 3  ; R 2  is hydroxy or carboxy which may be optionally esterized or amidated; R 3  is H or a lower alkyl; and n is 0 or an integer of 1 to 6 or a pharmaceutically acceptable salt thereof.

This application is a divisional, of application Ser. No. 07/286,857,filed Dec. 20, 1988 now U.S. Pat. No. 5,057,514.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having the formula (I):##STR2## wherein A is --CH₂ --, --O--, or --S--; R¹ is CH₃ or OCH₃ ; R²is hydroxy or carboxy which may be optionally esterized or amidated; R³is H or a lower alkyl; and n is 0 or an integer of 1 to 6, and an causedby cerebral ischemia cerebral insufficiency improver containing thesame.

The above-mentioned compounds (I) are effective for ameliorating andcuring (or treating) various symptoms based on cerebral organicdisorders as an oral medicine.

The term "cerebral organic disorders" used herein means various symptomsderived from cerebral ischemic diseases such as cerebral infarctsequela, cerebral hemorrhage sequela, and cerebral arteriosclerosissequela and various organic disorders derived from senile dementia,dementia presenilis, amnesia, cephalic traumatic sequela, and cerebraloperation sequela.

2. Description of the Related Art

The average human life-time has become prolonged, and the percentage ofold people in the population is increasing. Accompanying this increase,senile dementia such as memorial dementia characterized by a loss of thememory function as a primary symptom is becoming a serious socialproblem.

At present, a large number of therapeautic drugs for senile dementiahave been developed, but a satisfactory drug has not been developed yet.

The brain is an organ in which energy metabolism is most active, and ifa disorder in the oxygen supply mechanism within the brain occurs, andan oxygen deficiency state (cerebral hypoxia) continues in the braincells, a state will be finally reached in which no oxygen is supplied(cerebral anoxia). If such a state continues, the brain cells will beirreversibly damaged and will no longer be able to perform their normalfunctions.

At present, in the therapy of oxygen deficiency diseases accompanied bycerebral hypoxia or anoxia, a hypnolic such as phenobarbital has beenemployed, but the use thereof is limited because of the accompanyingside effects on respiratory organs or the circulatory system.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel compound havingeffective activities for a therapy of diseases caused by cerebralhypoxia or anoxia, by oral administration, and at low dose and lowtoxicity.

Other objects and advantages of the present invention will be apparentfrom the following description.

In accordance with the present invention, there is provided a novelcompound having the formula (I): ##STR3## wherein A is --CH₂ --, --O--,or --S--; R¹ is CH₃ or OCH₃ ; R² is hydroxy or carboxy which may beoptionally esterized or amidated; R³ is H or a lower alkyl; and n is 0or an integer of 1 to 6, preferably 0 or an integer of 1 to 3. It shouldbe noted that, although these compounds have the stereoisomers andoptical isomers, these isomers are also included within the scope of thepresent invention.

In accordance with the present invention, there is also provided acerebral insufficiency improver comprising, as an essential component, acompound having the above-mentioned formula (I) or a pharmaceuticallyacceptable salt thereof in a conventional pharmaceutically acceptablecarrier.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present inventors have found that the above-mentioned compounds (I)are very effective for a therapy of the above-mentioned diseases as aoral medicine at a low dose and with a low toxicity.

The compounds (I) according to the present invention can be prepared,for example, as follows.

The compounds (I-1) having a methylene group as a substituent A in theformula (I) can be prepared from the compounds of the compounds of theformulae (iii), (iv), (vi), and (ix), which can be prepared accordingto, for example, the following Routes A and B. ##STR4## wherein m is aninteger of 1 to 3; R^(4') is morpholino group, thiomorpholino group,piperidino group or N-methylpiperazinyl group; R⁵ is a lower alkyl.

Namely, according to Route A, by reacting α-tetralone with diethylcarbonate in the presence of a base (e.g., sodium hydroxide) at atemperature from room temperature to 100° C., ethyl1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate is obtained. Byreacting this with ethyl acrylate or a compound represented by theformula (VII): ##STR5## wherein X is a halogen atom, R⁵ is a lower alkylgroup and m is the same as defined above in a solvent which does notparticipate in the reaction, for example, ether, tetrahydrofuran,ethanol, in the presence of a base such as sodium hydride or sodiumethylate at 0° C. to room temperature. Thus,2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthalene alkylenecarboxylic acid ester is obtained.

This compound is hydrolyzed while refluxing under heating for 1 to 20hours in the presence of a base (e.g., sodium hydroxide, potassiumhydroxide, and sodium carbonate) in a mixture of an organic solvent(e.g., dioxane, tetrahydrofuran, ethanol) and water. Thereafter, the pHof the reaction mixture is adjusted by using an acid such asconcentrated hydrochloric acid to pH 1 to 2 to effect thedecarboxylation reaction to obtain a compound represented by the formula(i) in the Route A.

The compounds obtained above having m=1 or 2 are reduced with sodiumborohydride in a solvent which does not participate in the reaction,such as ethanol and methanol, at a temperature of from 0° C. to roomtemperature or catalytically reduced under hydrogen gas stream with theuse of palladium-carbon as a catalyst in a solvent such as, for example,dioxane, ethanol, methanol or tetrahydrofuran, followed bypost-treatment in a conventional manner, to obtain a compoundrepresented by the formula (ii) having m'=1 or 2. The resultant compoundcan be lactonized in a solvent such as toluene or benzene, in thepresence of a catalyst (e.g., hydrochloric acid, p-toluenesulfonic acid,D,L-camphorsulfonic acid) at room temperature to 150° C. or lactonizedwith the use of a dehydrating condensing agent (e.g.,dicyclohexylcarbodiimide, ethyl chlorocarbonate-triethylamine,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride) to obtaina compound represented by the formula (iii).

The compounds represented by the formula (iii) having m'=1 can beconverted to a compound represented by the formula (iv) by reacting withan alkylating agent such as methyl iodide in the presence of lithiumisopropylcyclohexylamide in a solvent which does not participate in thereaction such as tetrahydrofuran, benzene at a temperature of -78° C. to-30° C.

On the other hand, the compounds represented by the formula (i) havingm=3 can be converted to the compound represented by the formula (v) bycondensation with alcohols or amides, for example, morpholine orthiomorpholine, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride in a solvent which does not participate in the reactionsuch as methylene chloride or benzene.

The resultant compound (v) is reacted in a solvent which does notparticipate in the reaction such as ethanol, methanol by adding reducingagent, for example, sodium borohydride at a temperature of 0° C. to roomtemperature, to obtain the hydroxy compound.

This product is acetylated with acetic anhydride in the presence of abase such as 4-dimethylamino pyridine, pyridine in a solvent which doesnot participate in the reaction, such as methylene chloride, to obtainthe compound represented by the formula (vi).

According to Route B, a substituted benzaldehyde and succinic anhydrideare subjected to condensation together with a Lewis acid such as zincchloride and triethylamine in a solvent which does not participate inthe reaction at, for example, a temperature of 0° to 50° C., preferablyroom temperature, to form a butyrolactone carboxylic acid derivative,which compound is esterified to be converted to a lower alkyl ester,followed by catalytic reduction in the presence of palladium black orpalladium-carbon in an inert solvent such as dioxane, ethanol ortetrahydrofuran, whereby β-ethoxycarbonyl-γ-phenyl butyrate can beobtained. Next, this compound is subjected directly to ring closure byuse of a polyphosphoric acid, or alternatively, the compound isconverted to acid chloride by a conventional method and then subjectedto an intramolecular Friedel-Crafts reaction in the presence of a Lewisacid catalyst such as aluminum chloride or boron trifluoride-ethercomplex, whereby a compound represented by the formula (vii) can beobtained. As in the above-mentioned Route A, the compound (vii) can beconverted to the compound (viii), subsequently to the compound (ix).

The compound (iii), (iv) or (vi) obtained according to the Route A orthe compound (ix) obtained according to the Route B is condensed with ahydroquinone derivative having the formula (VIII): ##STR6## wherein R¹is as defined above, and then immediately oxidized with an oxidizingagent such as an aqueous ferric chloride, manganese dioxide or cericammonium nitrate, and subsequently amidated, esterified or reduced aconventional method, whereby the compound of the formula (I-1) having amethylene group as a substituent A in the formula (I) of the presentinvention can be obtained. ##STR7##

The compounds (I-2) in the present invention represented by the formula(I) having an oxygen atom as a substituent A can be prepared, forexample, as follows:

Namely, by heating o-methoxyacetophenone and pyrrolidine under reflux ina solvent such as benzene, in the presence of p-toluene sulfonic acid, acompound having the formula: ##STR8## is obtained. This compound isreacted with ethylbromoacetate or ethyl acrylate in a solvent which doesnot participate in the reaction, such as benzene or dioxane, and thenhydrolyzed in conventional manner, whereby o-methoxy benzoylalkylenecarboxylic acid ester is obtained. This ester derivative is treated witha Lewis acid such as aluminum chloride in a solvent which does notparticipate in the reaction, such as 1,2-dichloroethane, to be readilyconverted to a demethylated derivative.

The demethylated derivative is heated in N,N-dimethylformamide(hereinafter abbreviated as DMF) at about 100° C. in the presence of aboron trifluoride-ether complex for 5 to 30 hours, and thenmethanesulfonyl chloride is added, followed by heating at about 100° C.for 3 to 10 hours, whereby 4-oxo-1-chromene-3-alkylenecarboxylic acidester is obtained.

The above-mentioned ester can be converted to the corresponding hydroxylcompound, subsequently, lactone in the same manner as mentioned aboveand the compound represented by the general formula (x) can be obtained##STR9## wherein p is as defined above.

On the other hand, a known compound, 4-oxo-4H-1-benzopyran-2-carboxylicacid is esterified according to a conventional manner, and then, reducedto the compound, 4-hydroxy-4H-2,3-dihydro-1-benzopyran-2-carboxylic acidester.

The resultant ester is converted to the corresponding lactone is thesame manner as mentioned above to obtain the compound represented by theformula (xi). ##STR10## can be obtained.

The resultant compound (x) or (xi) is condensed with a hydroquinonederivative represented by the formula (VIII) and, in the same manner asmentioned above, the compound of the present invention represented bythe formula (I-2) having an oxygen atom as a substituent A in theformula (I) can be obtained.

Furthermore, the compound of the present invention represented by theformula (I-3) having a sulfur atom as a substituent A in the formula (I)can be prepared, for example, as follows.

Namely, a known compound, 4-oxo-1-thiocoumarone-3-methyl carboxylic acid(see JP-A-62-252789) is converted, in the same manner as mentionedabove, to the corresponding hydroxy compound, subsequently lactone.Thus, the compound having the formula (xii) can be obtained. ##STR11##

The resultant compound (xii) is condensed with the hydroquinonederivative having the formula (VIII) and, in the same manner asmentioned above, the compound of the present invention represented bythe formula (I-3) having a sulfur atom as a substituent A in the formula(I) is obtained.

The compounds having the general formula (I) according to the presentinvention can be orally administered alone or in combination withpharmaceutically acceptable conventional carriers and fillers in avariety of dosage forms such as tablets, troches, pills, granules,powders, capsules, and the like. The carriers include, for example,starch, dextrin, sucrose, lactose, silic acid, carboxymethylcellulose,cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calciumcarbonate, sodium bicarbonate, paraffin, cetyl alcohol, stearic acidesters, kaolin, bentonite, talc, calcium stearate, magnesium stearate,polyethyleneglycol, water, ethanol, isopropyl alcohol, andpropyleneglycol and the like.

Although there are no critical limitations to the content of thecompound (I) in the pharmaceutical preparation, the optimum content is1% to 90% by weight, more preferably 5% to 50% by weight.

Although there are no critical limitations to the dosage of the presentcerebral insufficiency improver, the optimum dosage of the compound (I)of the present invention is 0.1-1000 mg, preferably 10 to 500 mg, perday. This dosage can be suitably changed depending upon, for example,the characteristics of the subjects, including age, response, weight,severity of disease and the like, the dosage form, and the dosingfrequency.

EXAMPLES

The present invention now will be further illustrated by, but is by nomeans limited to, the following Synthesis Examples, and EvaluationExamples.

REFERENCE EXAMPLE 1 Synthesis of1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid (Compound No. R-1)##STR12##

A suspension of 10 g (0.0684 mole) of α-tetralone, 3.56 g (0.0890 mole)of 60% sodium hydride and 32 g (0.2709 mole) of diethyl carbonate washeated under reflux for 1 hour, then poured into water, adjusted withconc. hydrochloric acid to a pH of 1 to 2, and extracted with ether. Theether layer was washed with water and then dried over magnesium sulfate.After evaporation of the solvent, the crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=9/1) to obtain8.6 g of ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate, whichwas dissolved in tetrahydrofuran (220 ml) and then 1.90 g (0.0475 mole)of 60% sodium hydroxide was added under ice-cooling. After stirring for30 minutes, 10.0 g (0.0599 mole) of ethyl bromoacetate was added,followed by stirring for 3 hours at room temperature. The reactionmixture was poured into ice-water, extracted with ether, and then theextract was subjected to washing with water, drying and solventevaporation in a conventional manner. The crude product obtained waspurified by silica gel column chromatography (hexane/ethyl acetate=5/1)to obtain 9.03 g of the following ethyl2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetate ##STR13##

Then, this compound was heated under reflux in an aqueous 2N sodiumhydroxide solution (100 ml) and dioxane (50 ml) for 8 hours. Thereaction mixture was diluted with water, then adjusted to a pH of 1 to 2with conc. hydrochloric acid, and extracted with ether. After subjectingthe extract to washing with water, drying and solvent evaporation in aconventional manner, 5.4 g of the title compound was obtained.

REFERENCE EXAMPLE 2 Synthesis of1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropionic acid (Compound No. R-2)##STR14##

5.0 g (0.0229 mole) of ethyl1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate obtained in ReferenceExample 1 was added into an ethanolic (300 ml) solution of sodiumethoxide prepared from 158 mg (6.8695 mmole) of sodium, and then 2.99 g(0.0299 mole) of ethyl acrylate was added, followed by stirring at roomtemperature for 4 hours.

The reaction mixture was concentrated under a reduced pressure, dilutedwith water, and then extracted with ether. The extract was subjected towashing with water, drying and solvent evaporation in a conventionalmanner to obtain 5.6 g of ethyl2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropionate.

This compound was heated under reflux in an aqueous 2N sodium hydroxidesolution (200 ml) and dioxane (100 ml) for 8 hours. The reaction mixturewas diluted with water, then adjusted to a pH of 1 to 2 with conc.hydrochloric acid and extracted with ether. After subjecting the extractto washing with water, drying and solvent evaporation in a conventionalmanner, 3.71 g of the title compound was obtained.

Reference Example 3 Synthesis of1,2,3,4-tetrahydro-1-oxo-2-naphthalenebutyric acid (Compound No. R-3)##STR15##

10.0 g (45.8715 mmole) of ethyl1,2,3,4-tetrahydro-1-oxo-2-naphthalenecarboxylate obtained in ReferenceExample 1 was dissolved in 50 ml of 1,2-dimethoxy ethane and thesolution was added to the suspension of 2.3 g of 60% sodium hydride in250 ml of 1,2-dimethoxy ethane under ice-cooling.

Then, 14.4 g (71.773 mmole) of ethyl 4-bromobutyrate was added to theabove solution. After the mixture was refluxed for 6 hours, the reactionmixture was poured in ice-water, followed by extracting with ether. Theextracted solution was washed with water and dried in a conventionalmanner. After evaporation of the solvent, the crude product was purifiedby silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain6.86 g of ethyl2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthalenebutyrate, whichwas dissolved in a mixture of 2N aqueous sodium hydroxide solution (160ml) and dioxane (40 ml), followed by heating under reflux with stirringfor 16 hours.

The reaction mixture was diluted with water and, after adjusting the pHto 1 to 2 with conc. hydrochloric acid, was extracted with ether. Theextracted solution was washed with water, dried, and concentrated in aconventional manner to obtain 3.98 g of the title compound.

Reference Example 4 Synthesis of ethyl1,2,3,4-tetrahydro-4-oxo-2-naphthoate (Compound No. R-4) ##STR16##

To a suspension of 10.6 g (0.1000 mole) of benzaldehyde, 15.0 g (0.1500mole) of succinic anhydride and 30.0 g (0.2206 mole) of zinc chloride inmethylene chloride (120 ml) was added, and then, after addition of 20.2g (0.2000 mole) of triethylamine, and the mixture was stirred at roomtemperature for 16 hours.

To the reaction mixture 2N aqueous hydrochloric acid (500 ml) was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water, dried and then the solvent was evaporated. The crudeproduct obtained was recrystallized from chloroform to obtain 13.13 g ofβ-carboxy-γ-phenyl-γ-butyrolactone as a mixture of cis-isomer andtrans-isomer. ##STR17##

A methylene chloride solution (200 ml) of 3.25 g (15.758 mmole) of thecompound obtained above (a mixture of cis- and trans-isomers), 867 mg(18.8478 mmole) of ethanol, 6.04 g (31.5075 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 193 mg(1.5819 mmole) of 4-dimethylaminopyridine was stirred at roomtemperature for 8 hours.

The reaction mixture was washed with water, then dried and the solventwas evaporated. The crude product obtained was purified by silica gelcolumn chromatography (hexane/ethyl acetate=3/1) to obtain 3.30 g ofβ-ethoxycarbonyl-γ-phenyl-γ-butyrolactone as a mixture of cis-isomer andtrans-isomer.

A suspension of 1.0 g of palladium chloride in dioxane (40 ml) wasstirred under a hydrogen gas stream at room temperature for 20 minutes.Next, a solution of 3.30 g of (14.1025 mmole) of the compound obtainedabove in dioxane (5 ml) was added and the mixture was stirred under ahydrogen gas stream at room temperature for 16 hours.

By filtering the reaction mixture and concentrating the filtrate under areduced pressure, 3.32 g of β-ethoxycarbonyl-γ-phenylbutyric acid wasobtained.

An amount of 1.30 g (5.5080 mmole) of the compound obtained above wasadded to oxalyl chloride (20 ml) and stirred at room temperature for 5hours.

The reaction mixture was concentrated under a reduced pressure, theresidue was dissolved in 1,2-dichloethane (70 ml), and 806 mg (6.0601mmole) of aluminum chloride was added under ice-cooling, followed bystirring at room temperature for 16 hours. The reaction mixture waspoured into 1N aqueous hydrochloric acid, and extracted with ether. Theorganic layer was washed with water, dried and then the solvent wasevaporated. The crude product was purified by silica gel chromatography(hexane/ethyl acetate=2/1) to obtain 864 mg of the title compound.

Reference Example 5 Synthesis of ethyl 4-oxo-1-chromene-3-acetate(Compound No. R-5) ##STR18##

An amount of 15 g (0.1000 mole) of o-methoxyacetophenone, 7.8 g (0.1097mole) of pyrrolidine and 100 mg (0.526 mmole) of p-toluenesulfonic acidmonohydrate were dissolved in benzene, and the benzene solution (60 ml)was heated under reflux for 14 hours and superfluous solvent wasevaporated by concentration under a reduced pressure. To the residueobtained, benzene (100 ml) and 25 g of ethylbromoacetate (0.1500 mole)were added, and the mixture was heated under reflux for 4 hours.

The reaction mixture was cooled, then concentrated under a reducedpressure and the residue obtained was dissolved in a mixture ofmethanol/water=100 ml/20 ml. The solution was heated under reflux for 2hours, then methanol was evaporated under a reduced pressure, andthereafter, the reaction mixture was diluted with water and extractedwith ether.

The extract layer obtained was washed with dil. hydrochloric acid,saturated aqueous sodium chloride and dried over anhydrous magnesiumsulfate, followed by concentration under a reduced pressure.

The crude product obtained was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1) to obtain 8.3 g of ethylo-methoxybenzoylpropionate. ##STR19##

This compound was dissolved in methylene chloride and to the solution(250 ml), 16.5 g (0.124 mole) of aluminum chloride was added underice-cooling. After stirring at room temperature for 5 hours, thereaction mixture was diluted with cold dil. hydrochloric acid, followedby extraction with chloroform.

The extract layer obtained was washed with water, then dried and thesolvent was evaporated to obtain 6.8 g of ethylo-hydroxybenzoylpropionate.

This compound was then dissolved in DMF (39 ml), and to the solution, 23ml of boron trifluoride-diethyl ether was added under ice-cooling. Afterstirring at room temperature for 30 minutes, the mixture was furtherstirred at 100° C. for 14 hours. Next, to the reaction mixture was added10.8 g (0.083 mole) of methanesulfonyl chloride, and after heating underreflux for 6 hours, the reaction mixture was diluted with ice-water andextracted with ether.

The extract layer obtained was washed with water, dried and the solventwas evaporated. The residue obtained was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1) to obtain 5.0 g of the titlecompound.

REFERENCE EXAMPLE 6 Synthesis of ethyl 4-oxo-1-chromene-3-propionate(Compound No. R-6) ##STR20##

Similarly as in Reference Example 5, 10 g (0.067 mole) ofo-methoxyacetophenone, 5.21 g (0.073 mole) of pyrrolidine, and 50 mg(0.263 mmole) of p-toluenesulfonic acid monohydrate were dissolved inbenzene (60 ml), the benzene solution was heated under reflux for 16hours, and superfluous solvent was evaporated by concentration under areduced pressure. To the residue obtained were added 40 ml of dioxaneand 10 g (0.100 mole) of ethyl acrylate, and the mixture was heatedunder reflux for 3 hours.

The reaction mixture was cooled, 10 ml of water was added and themixture was heated under reflux for one hour, followed by concentrationunder a reduced pressure. The residue was diluted with ice-water, andthen extracted with ether.

The extract layer obtained was washed with dil. hydrochloric acid andsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate, followed by concentration under a reduced pressure.

The crude product obtained was purified by silica gel columnchromatography (hexane/ethyl acetate=5/1) to obtain 6.3 g of ethylo-methoxybenzoylbutyrate. ##STR21##

This compound was dissolved in 1,2-dichloroethane, and to the solution(250 ml), 10.07 g (0.076 mole) of aluminum chloride was added underice-cooling, and the mixture was stirred at room temperature for 3hours. Next, the reaction mixture was diluted with cold dil.hydrochloric acid and then extracted with chloroform.

The extract layer obtained was washed with water, then dried and thesolvent was evaporated to obtain 5.41 g of ethylo-hydroxybenzoylbutyrate.

This compound was dissolved in DMF (29 ml), to the solution was added 17ml of boron trifluoride-diethyl ether under ice-cooling, and afterstirring at room temperature for 30 minutes, the mixture was heatedunder reflux for 20 hours. Next, 7.9 g (69 mmole) of methanesulfonylchloride was added to the reaction mixture, and after heating underreflux for 4 hours, the reaction mixture was diluted with ice-water andextracted with ether.

The extract layer obtained was washed with water, dried and then thesolvent was evaporated. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1) to obtain 4.07 g of the titlecompound.

REFERENCE EXAMPLE 7 Synthesis of2,3,3a,4,5,9b-hexahydronaphtho[1,2-b]furan-2-one (Compound No. R-7)##STR22##

To an ethanol solution (100 ml) of 4.0 g (0.0196 mole) of the compoundof Reference Example 1, 2.24 g (0.0589 mole) of sodium borohydride wasadded at 0° C., and the mixture was stirred at room temperature for 5hours.

The reaction mixture was concentrated under a reduced pressure, thendiluted with water, adjusted to a pH of 1 to 2 with conc. hydrochloricacid, and thereafter, extracted with ether. The extract was treated in aconventional manner, the crude product was then dissolved in methylenechloride (220 ml), and to the resultant solution was added 9.31 g(0.0486 mole) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride, followed by stirring at room temperature for 3 hours.

The reaction mixture was washed with water, dried and the solvent wasevaporated. The crude product obtained was purified by silica gelchromatography (hexane/ethyl acetate=5/2) to obtain two isomers (R-7a,R-7b) of the title compound in amounts of 1.91 g and 0.64 g,respectively.

REFERENCE EXAMPLE 8 Synthesis of2,3,3a,4,5,9b-hexahydro-3-methylnaphtho[1,2-b]furan-2-one (Compound No.R-8) ##STR23##

A solution of 1.0 g (5.319 mmole) of the compound of Reference Example 7(R-7a) in THF (5 ml) was added, with stirring, to a THF solution (20 ml)of lithium isopropylcyclohexylamide, prepared from 750 mg (5.319 mmole)of isopropylcyclohexylamine and 3.39 ml of n-butyl lithium in hexanesolution (1.57 mol/l) at a temperature of -78° C., followed by stirringat the same temperature for 30 minutes.

Next, a THF solution (5 ml) of 793 mg (5.5868 mmole) of methyl iodidewas added thereto, followed by further stirring for 2 hours. Afterstirring, the reaction mixture was poured in water, followed byextracting with ether. The extracted layer was washed with a saturatedsodium chloride solution, dried over magnesium sulfate. Afterevaporating the solvent, the crude product thus obtained was purified bysilica gel chromatography (hexane/ethyl acetate=6/1) to obtain 430 mg ofthe title compound (R-8a).

Similarly, 483 mg of the title compound (R-8b) was obtained from 1.0 gof the compound R-7b.

REFERENCE EXAMPLE 9 Synthesis of3,4,4a,5,6,10-hexahydro-2H-naphtho[1,2-b]pyran-2-one (Compound No. R-9)##STR24##

To an ethanol solution (80 ml) of 3.81 g (0.0175 mole) of the compoundof Reference Example 2, 2.00 g (0.0526 mole) of sodium borohydride wasadded at 0° C., and the mixture was stirred for 5 hours.

The reaction mixture was concentrated under a reduced pressure, thendiluted with water, adjusted to a pH of 1 to 2 with conc. hydrochloricacid, and thereafter, extracted with ether. The extract was treated inconventional manner, the crude product was then dissolved in methylenechloride (400 ml), and to the resultant solution, 7.93 g (0.0414 mole)of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride wasadded, followed by stirring at room temperature for 3 hours.

The reaction mixture was washed with water, dried and the solvent wasevaporated. The crude product obtained was purified by silica gelchromatography (hexane:ethyl acetate=5:2) to obtain two isomers (R-9a,(R-9b) of the title compound in amounts of 1.33 g and 0.57 g,respectively.

REFERENCE EXAMPLE 10-(1) Synthesis of1-acetoxy-2-(4-thiomorpholino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene(Compound No. R-10-(1)) ##STR25##

An amount of 620 mg (3.234 mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a methylene chloride solution(30 ml) of 499 mg (2.151 mmole) of the compound R-3 obtained inReference Example 3 and 276 mg (2.680 mmole) of thiomorpholine, followedby stirring at room temperature for 3 hours.

The reaction mixture was washed with 1N hydrochloric acid and asaturated aqueous sodium chloride solution and dried. The solvent wasdistilled off to obtain 654 mg of1-oxo-2-(4-thiomorpholino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene.##STR26##

This compound was dissolved in an ethanol solution and sodiumborohydride was added thereto under ice-cooling, followed by stirring atroom temperature for 6 hours. Then, the reaction mixture wasconcentrated under a reduced pressure, diluted with dil. hydrochloricacid, and extracted with ether. The extracted layer was washed withwater and the solvent was distilled off. The resultant residue wasdissolved in methylene chloride and, to the solution, pyridine, aceticanhydride and dimethylamino pyridine were added, followed by stirring atroom temperature for 16 hours.

The reaction mixture was washed with 1N hydrochloric acid and an aqueoussaturated sodium chloride solution and dried, followed by concentratingunder a reduced pressure.

The resultant crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1) to obtain 600 mg of the titlecompound.

REFERENCE EXAMPLE 10-(2) Synthesis of1-acetoxy-2-(4-morpholino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene(Compound No. R-10-(2))

1-Oxo-2-(4-morpholino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene wasobtained according to Reference Example 10-(1) by using morpholineinstead of thiomorpholine.

Thereafter, the resultant compound was similarly acetylated and waspurified by silica gel column chromatography (hexane/ethyl acetate=5/3)to obtain the title compound.

REFERENCE EXAMPLE 10-(3) Synthesis of1-acetoxy-2-(4-piperidino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene(Compound No. R-10-(3))

1-Oxo-2-(4-pyperidino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene wasobtained, according to Reference Example 10-(1), by using piperidineinstead of thiomorpholine.

Thereafter, the resultant compound was similarly acetylated and waspurified by silica gel column chromatography (methylenechloride/acetone=50/1) to obtain the title compound.

REFERENCE EXAMPLE 11 Synthesis of2,3-benzo-6-oxo-7-oxabicyclo[3,2,1]-octane (Compound No. R-11) ##STR27##

To a solution of 2.88 g (13.2110 mmole) of the compound of ReferenceExample 4 in ethanol (80 ml), 1.51 g (39.7368 mmole) of sodiumborohydride was added under ice-cooling, and the mixture was stirred for4 hours.

The reaction mixture was concentrated under a reduced pressure, theresidue was diluted with 2N aqueous hydrochloric acid and extracted withether. The organic layer was washed with water, dried and concentratedunder a reduced pressure to give 2.76 g of ethyl1,2,3,4-tetrahydro-4-hydroxy-2-naphthoate as a mixture of cis-isomer(over 90%) and trans-isomer. ##STR28##

To a solution of the resultant compound in dioxane (50 ml), 3% aqueouspotassium hydroxide (100 ml) was added and the mixture was stirred atroom temperature for 8 hours.

The reaction mixture was diluted with water, adjusted to a pH of 1 to 2with conc. hydrochloric acid, and extracted with ether. The extractobtained was washed with water, dried over magnesium sulfate, andfurther concentrated under a reduced pressure. The residue obtained wasdissolved in methylene chloride (500 ml) and 5.03 g (26.227 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added,followed by stirring at room temperature for 4 hours. The reactionmixture was washed with water, dried and then the solvent wasevaporated. The crude product was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to obtain 971 mg of the titlecompound.

REFERENCE EXAMPLE 12 Synthesis of2,3,3aα,9bβ-tetrahydro-2-oxofurano[4,5-c]-1-chroman (Compound No. R-12a)and 2,3,3aα,9bα-tetrahydro-2-oxofurano-[4,5-c]-1-chroman (Compound No.R-12b) ##STR29##

An amount of 1.65 g (7.112 mmole) of the compound of Reference Example 5was dissolved in ethanol, and the solution (100 ml) was stirred under ahydrogen gas stream in the presence of 800 mg of 5% palladium-carbon for3 days.

Next, after the reaction mixture was filtered, the filtrate wasconcentrated under a reduced pressure and the residue obtained wassubjected to silica gel column chromatography (hexane/ethyl acetate=2/1)for purification to obtain 1.43 g of ethyl 4-hydroxy-1-chroman-3-acetateas a mixture of the isomers.

This compound was dissolved in dioxane (5 ml), and to the solution wasadded 5% aqueous potassium hydroxide (20 ml), and the mixture was heatedunder reflux for 3 hours.

The reaction mixture was cooled, diluted with water, and the liquidproperty was made acidic (pH=1 to 2) by an addition of conc.hydrochloric acid, followed by ether extraction.

The ether layer obtained was washed with water, dried over magnesiumsulfate, and the solvent was evaporated. The crude product obtained wasdissolved in dichloromethane (300 ml), 2.79 g (14.554 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added,and the mixture was stirred at room temperature for 3 hours.

The reaction mixture was washed with water, dried over magnesium sulfateand concentrated under a reduced pressure. The crude product obtainedwas purified by silica gel column chromatography (hexane/ethylacetate=2/1) to obtain 590 mg of the title compound R-12a and 278 mg ofR-12b.

REFERENCE EXAMPLE 13 Synthesis of3,4,4aα,10bβ-tetrahydro-2-oxopyrano[5,6-c]-1-chroman (Compound No.R-13a) and 3,4,4aα,10bα-tetrahydro-2-oxopyrano[5,6-c]-1-chroman(Compound No. R-13b) ##STR30##

An amount of 5.55 g (22.561 mmole) of the compound of Reference Example6 was dissolved in ethanol, and the solution (150 ml) was stirred undera hydrogen gas stream in the presence of 5% palladium-carbon (1000 mg)for 3 days.

Next, after the reaction mixture was filtered, the filtrate wasconcentrated under a reduced pressure, and the residue obtained waspurified by silica gel column chromatography (hexane/ethyl acetate=3/1)to obtain ethyl 4-hydroxy-1-chroman-3-propionate as 1.59 g of transisomer and 1.87 g of cis isomer. ##STR31##

An amount of 1.59 g (6.360 mmole) of the resultant ethyl4α-hydroxy-1-chroman-3β-propionate was dissolved in dioxane (15 ml), andto this solution, 5% aqueous potassium hydroxide (50 ml) was added andthe mixture was heated under reflux for 2 hours.

The reaction mixture was cooled, diluted with water, and then the liquidproperty was made acidic (pH=1 to 2) by an addition of conc.hydrochloric acid, followed by ether extraction.

The extract layer obtained was washed water, dried over magnesiumsulfate, and then concentrated under a reduced pressure. The residueobtained was dissolved in dichloromethane (500 ml), 3.58 g (18.675mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridewas added, and the mixture was stirred at room temperature for 4 hours.

The reaction mixture was washed with water, dried over magnesiumsulfate, and then concentrated under a reduced pressure. The crudeproduct obtained was purified by silica gel chromatography (hexane/ethylacetate=2/1) to obtain 988 mg of the title compound R-13a.

Similarly, from ethyl 4α-hydroxy-a-chroman-3α-propionate, the titlecompound R-13b was obtained.

REFERENCE EXAMPLE 14 Synthesis of3,4-benzo-7-oxo-2,6-dioxabicyclo[3,2,1]octane (Compound No. R-14)##STR32##

To an ethanol solution (200 ml) of 1.5 g (6.8807 mmole) ofchromane-2-carboxylic acid, 200 mg of 5% palladium-carbon was added andthe mixture was stirred at room temperature for 5 days.

The reaction mixture was filtered and the filtrate was concentratedunder a reduced pressure. The resultant residue was purified by silicagel column chromatography (hexane/ethyl acetate=1/1) to obtain 520 mg of2-ethoxycarbonyl-4-hydroxy-benzopyran.

To an ethanol solution (10 ml) of the compound obtained above, 20 ml of3% aqueous potassium hydroxide was added, and the mixture was stirred atroom temperature for one hour.

The reaction mixture was diluted with water, then washed with ether, andsubsequently, the aqueous layer was adjusted to a pH of 1 to 2 withconc. hydrochloric acid, followed by extraction with ether. The etherlayer was washed with water, dried, and then concentrated under areduced pressure. Thereafter, the residue was suspended in methylenechloride (30 ml), 660 mg (3.4428 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added,and the mixture was stirred at room temperature for one hour.Subsequently, the reaction mixture was washed with water, dried, andthen concentrated under a reduced pressure. The residue obtained waspurified by silica gel column chromatography (hexane/ethyl acetate=2/1)to obtain 282 mg of the title compound.

REFERENCE EXAMPLE 15 Synthesis of2,3,3aα,9bβ-tetrahydro-2-oxofurano[4,5-c]-1-thiochroman (Compound No.R-15a) and 2,3,3aα,9bα-tetrahydro-2-oxofurano-[4,5-c]-1-thiochroman(Compound No. R-15b) ##STR33##

To an ethanol solution (60 ml) of 1.47 g (6.622 mmole) of4-oxo-1-thiochroman-3-acetic acid, 629 mg (16.553 mmole) of sodiumborohydride was added at 0° C., and the mixture was stirred at the sametemperature for 2 hours. The reaction mixture was concentrated under areduced pressure, and the residue was diluted with water, adjusted to apH of 1 to 2 with conc. hydrochloric acid and then extracted with ether.The extract layer was washed with water, dried over magnesium sulfate,and the solvent was evaporated. The crude product obtained was dissolvedin methylene chloride (400 ml), then 3.17 g (16.536 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added,and the mixture was stirred at room temperature for 4 hours. Thereaction mixture was washed with water, dried, and the solvent wasevaporated. The crude product obtained was purified by silica gelchromatography (hexane/ethyl acetate=3/1) to obtain 582 mg of the titlecompound R-15 a and 420 mg of R-15b.

The physicochemical data of the compounds synthesized in the aboveReference Examples 1 to 15 are shown in Table 1.

WORKING EXAMPLE 1 Synthesis of1-(3,4-dimethoxy-6-methyl-2,5-benzoquinoyl)-1,2,3,4-tetrahydro-2-naphthaleneaceticacid (Compound No. 1)

To a 1,2-dichloroethane solution (20 ml) of 500 mg (2.6595 mmole) of thecompound of Reference Example 7 (Compound No. R-7a) and 636 mg (3.4565mmole) of 2,3-dimethoxy-5-methyl-1,4-hydroquinone, 566 mg (3.9878 mmole)of boron trifluoride-ether complex was added, and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasconcentrated under a reduced pressure, then dissolved in a mixture ofacetonitrile (15 ml) and water (5 ml) and 4.74 g (8.6496 mmole) of cericammonium nitrate (hereinafter called CAN) followed by stirring at roomtemperature for 30 minutes.

The reaction mixture was diluted with water, extracted with ether, andthe extract was washed with water, and dried, followed by evaporation ofthe solvent. The crude product obtained was purified by silica gelchromatography (3%-5% methanol/dichloromethane) to obtain 620 mg of thetitle compound.

WORKING EXAMPLE 2 Synthesis of1-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-1,2,3,4-tetrahydro-2-naphthalene-propionicacid (Compound No. 2)

To a 1,2-dichloroethane solution (20 ml) of 500 mg (2.4752 mmole) of thecompound of Reference Example 9 (Compound No. R-9a) and 592 mg (3.2173mmole) of 2,3-dimethoxy-5-methyl-1,4-hydroquinone, 526 mg (3.7060 mmole)of boron trifluoride-ether complex was added, and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasconcentrated under a reduced pressure, dissolved in a mixed solution ofacetonitrile (15 ml) and water (5 ml), and 3.4 g (6.2043 mmole) of CANwas added, followed by stirring at room temperature for 30 minutes. Thereaction mixture was diluted with water, then extracted with ether, andthe extract was washed with water, dried and the solvent was evaporated.The crude product was purified by silica gel chromatography (3-5%methanol/dichloromethane) to obtain 520 mg of the title compound.

WORKING EXAMPLE 3 Synthesis of1-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-2-(2-thiomorpholino-2-oxoethyl)-1,2,3,4-tetrahydronaphthalene(Compound No. 3)

To a methylene chloride solution (20 ml) of 348 mg (0.9405 mmole) of thecompound of Working Example 1 (Compound No. 1) and 145 mg (1.4077 mmole)of thiomorpholine 270 mg (1.4084 mmole) of1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added,and the mixture was stirred at room temperature for 6 hours.

The reaction mixture was washed with water, dried and the solvent wasevaporated. The crude product obtained was purified by silica gelchromatography (hexane/ethyl acetate=1/1) to obtain 270 mg of the titlecompound.

WORKING EXAMPLE 4-10

Compound Nos. 4 to 10 were prepared from the compound Nos. 1 and 2according to a method in Working Example 3.

WORKING EXAMPLE 11 Synthesis of1-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-2-(4-thiomorpholino-4-oxobutyl)-1,2,3,4-tetrahydronaphthalene(Compound No. 11)

To a solution of 600 mg (1.662 mmole) of the compound R-10-(1) obtainedin Reference Example 10 and 397 mg (2.158 mmole) of2,3-dimethoxy-5-methyl-1,4-hydroquinone in 1,2-dichloroethane (8 ml), 80μl of trifluoromethane sulfonic acid was added, followed by stirring atroom temperature for 16 hours.

The reaction mixture was diluted with water followed by adding 0.4 g ofmanganese dioxide. After stirring at room temperature for 30 minutes,the mixture was subjected to ultrafiltration. The filtrate wasconcentrated under a reduced pressure. The crude product obtained waspurified by silica gel chromatography (hexane/ethyl acetate=2/1) toobtain 238 mg of the title compound.

WORKING EXAMPLES 12 AND 13

Compound Nos. 12 and 13 were prepared according to a method in WorkingExample 11.

The structures of these compounds No. 1 to 13 are as follows.

    ______________________________________                                         ##STR34##                    (II)                                            Compound                                                                      No.            m     R.sup.4                                                  ______________________________________                                        1              1     OH                                                       2              2     OH                                                       3              1                                                                                    ##STR35##                                               4              1                                                                                    ##STR36##                                               5              1                                                                                    ##STR37##                                               6              1                                                                                    ##STR38##                                               7              1     OEt                                                      8              2                                                                                    ##STR39##                                               9              2                                                                                    ##STR40##                                               10             2     OEt                                                      11             3                                                                                    ##STR41##                                               12             3                                                                                    ##STR42##                                               13             3                                                                                    ##STR43##                                               ______________________________________                                    

WORKING EXAMPLE 14 Synthesis of1,2,3,4-tetrahydro-4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-2-naphtoicacid (Compound No. 14a, 14b)

To a solution of 654 mg (3.5543 mmole) of2,3-dimethoxy-5-methyl-1,4-hydroquinone and 476 mg (2.7356 mmole) of thecompound (R-11) of Reference Example 11 dissolved in 1,2-dichloroethane(20 ml), 582 mg (4.1006 mmole) of boron trifluoride-ether complex wasadded at room temperature, and the mixture was stirred for 16 hours.

The reaction mixture was concentrated under a reduced pressure, theresidue was dissolved in a mixture of acetonitrile (15 ml) and water (5ml), and 4.87 g (8.8868 mmole) of ceric ammonium nitrate was added,followed by stirring at room temperature for 30 minutes. The reactionmixture was poured into water and extracted with ether. The extract waswashed with water, dried and then the solvent was evaporated. Theresidue obtained was purified and separated by silica gel columnchromatography (5% methanol/dichloromethane) to obtain 120 mg of thestereoisomer 14a (cis-isomer), 83 mg of 14b (trans-isomer) and 450 mg ofa mixture of 14a and 14b.

WORKING EXAMPLES 15-18

The following compounds 15-18 (i.e., cis-isomers 15a-18a andtrans-isomers 15b-18b were prepared from Compound No. 14 according tothe method of Working Example 3.

    ______________________________________                                         ##STR44##                    (III)                                           Compound                                                                      No.          R.sup.4                                                          ______________________________________                                        14           OH                                                               15                                                                                          ##STR45##                                                       16                                                                                          ##STR46##                                                       17                                                                                          ##STR47##                                                       18                                                                                          ##STR48##                                                       ______________________________________                                    

WORKING EXAMPLE 19 Synthesis of(±)-4β-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-1-chroman-3.alpha.-aceticacid (Compound No. 19)

To a solution of 750 mg (3.947 mmole) of the compound (R-12b) ofReference Example 12 and 872 mg (4.739 mmol) of2,3-dimethoxy-5-methyl-1,4-hydroquinone dissolved in 1,2-dichloroethane,728 mg (5.129 mmole) of boron trifluoride-ether complex was added, andthe mixture was stirred at room temperature for 15 hours. Subsequently,the reaction mixture was concentrated under a reduced pressure and theresidue was dissolved in tetrahydrofuran (30 ml). Into the solution, 10%aqueous ferric chloride (30 ml) was added and the mixture was stirred atroom temperature for 30 minutes. After stirring, the reaction mixturewas diluted with water, and extracted with ether. The extract layer waswashed with water, dried over magnesium sulfate, and the solvent wasevaporated. The crude product obtained was subjected to silica gelcolumn chromatography (5% methanol/methylene chloride) for purificationto obtain 800 mg of the title compound.

Similarly, from 350 mg of R-12a, 258 mg of the title compound wasobtained.

WORKING EXAMPLE 20 Synthesis of(±)-4β-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-1-chroman-3.alpha.-propionicacid (Compound No. 20)

To a solution of 800 mg (3.922 mmole) of the compound (R-13b) ofReference Example 13 and 794 mg (4.315 mmole) of2,3-dimethoxy-5-methyl-1,4-hydroquinone dissolved in 1,2-dichloroethane,835 mg (5.883 mmole) of boron trifluoride-ether complex was added, andthe mixture was stirred at room temperature for 20 hours. Next, thereaction mixture was concentrated under a reduced pressure, the residueobtained was dissolved in methylene chloride and 1.5 g of manganesedioxide was added, followed by stirring for 3 hours. The reactionmixture was filtered, and the filtrate was concentrated under a reducedpressure. The residue obtained was subjected to silica gel columnchromatography (5% methanol/methylene chloride) for purification toobtain 310 mg of the title compound.

WORKING EXAMPLES 21-25

The following compounds 21 to 25 were prepared from the compound 19 and20 according to a method of Working Example 3.

    ______________________________________                                         ##STR49##                    (IV)                                            Compound                                                                      No.            p     R.sup.4                                                  ______________________________________                                        19             1     OH                                                       20             2     OH                                                       21             1                                                                                    ##STR50##                                               22             1                                                                                    ##STR51##                                               23             1                                                                                    ##STR52##                                               24             2                                                                                    ##STR53##                                               25             2                                                                                    ##STR54##                                               ______________________________________                                    

WORKING EXAMPLE 26 Synthesis of2-carboxy-4-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-chroman (CompoundNo. 26)

To a 1,2-dichloroethane solution (40 ml) of 870 mg (4.7282 mmole) of2,3-dimethoxy-5-methyl-1,4-hydroquinone, 610 mg (4.2978 mmole) of borontrifluoride ether complex was added, and after the mixture was stirredfor 15 minutes, 756 mg (4.2954 mmole) of the compound (R-14) ofReference Example 14 was added, followed by stirring at room temperaturefor 16 hours.

Then, after the reaction mixture was concentrated under a reducedpressure, the residue was dissolved in tetrahydrofuran (30 ml), 10%aqueous ferric chloride (30 ml) was added, and the mixture was stirredat room temperature for one hour. The reaction mixture was concentratedunder a reduced pressure, excessive tetrahydrofuran evaporated, and thenthe reaction mixture was diluted with water, followed by extraction withether. The ether layer was washed with water, dried, then concentratedunder a reduced pressure, and the residue was purified by silica gelcolumn chromatography (5% methanol/dichloromethane) to obtain 520 mg ofthe title compound.

WORKING EXAMPLE 27-28

The following compounds 27 and 28 were prepared from the compound 26according to a method of Example 3.

    ______________________________________                                         ##STR55##                                                                    Compound                                                                      No.           R.sup.4                                                         ______________________________________                                        26            OH                                                              27                                                                                           ##STR56##                                                      28                                                                                           ##STR57##                                                      ______________________________________                                    

WORKING EXAMPLE 29 Synthesis of(±)-4β-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-1-thiochroman-3.alpha.-aceticacid (Compound No. 29)

To a solution of 500 mg (2.427 mmole) of the compound R-15a of ReferenceExample 15 and 447 mg (2.429 mmole) of2,3-dimethoxy-5-methyl-1,4-dihydroquinone dissolved in1,2-dichloroethane (40 ml), 448 mg (3.159 mmole) of borontrifluoride-ether complex was added, and the mixture was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated under areduced pressure, and then dissolved in methylene chloride (60 ml),followed by an addition of 1.06 g (12.192 mmole) of manganese dioxideand stirring at room temperature for 6 hours. The reaction mixture wasfiltered, and the crude product obtained by concentration of thefiltrate under a reduced pressure was subjected to silica gel columnchromatography (5% methanol/methylene chloride) for purification toobtain 340 mg of the title compound.

Although R-15b was used instead of R-15a, the title compound was stillobtained.

WORKING EXAMPLES 30-32

The following compounds were prepared from the compound 29 according toa method of Working Example 3.

    ______________________________________                                         ##STR58##                                                                    Compound                                                                      No.          R.sup.4                                                          ______________________________________                                        29           OH                                                               30                                                                                          ##STR59##                                                       31                                                                                          ##STR60##                                                       32                                                                                          ##STR61##                                                       ______________________________________                                    

WORKING EXAMPLE 33 Synthesis of1-(3,4-dimethoxy-6-methyl-2,5-benzoquinonyl)-1,2,3,4-tetrahydro-2-naphthaleneisopropionicacid (Compound No. 33)

To a 1,2-dichloroethane solution (20 ml) of 400 mg (1.9801 mmole) of thecompound of Reference Example 8 (Compound No. R-8a) and 364 mg (1.9782mmole) of 2,3-dimethoxy-5-methyl-1,4-hydroquinone, 365 mg (2.5716 mmole)of boron trifluoride-ether complex was added, and the mixture wasstirred at room temperature for 12 hours. The reaction mixture wasconcentrated under a reduced pressure, then dissolved in a mixture ofacetonitrile (15 ml)-water (5 ml) and 2.71 g (4.9452 mmole) of CAN wasadded, followed by stirring at room temperature for 20 minutes. Thereaction mixture was diluted with water, then extracted with ether, andthe extract was washed with water, dried and the solvent was evaporated.The crude product was purified by silica gel chromatography (5%methanol-methylene chloride) to obtain 364 mg of the title compound(33-a).

Similarly, 372 mg of the title compound (33-b) was obtained from 400 mgof the compound R-8b. ##STR62##

WORKING EXAMPLES 34-35

The following compounds 34, 35, 34a, 34b, 35a, and 35b were preparedfrom the compound 33 according to a method of Working Example 3.

    ______________________________________                                         ##STR63##                                                                    Compound                                                                      No.           R.sup.4                                                         ______________________________________                                        33            OH                                                              34                                                                                           ##STR64##                                                      35                                                                                           ##STR65##                                                      ______________________________________                                    

WORKING EXAMPLE 36 Synthesis of1-(3,4,5-trimethyl-2,5-benzoquinonyl)-1,2,3,4-tetrahydro-2-naphthaleneaceticacid (Compound No. 36)

To a methylene chloride solution (50 ml) of 1.35 g (7.181 mmole) of thecompound of Reference Example 7 (R-7a:R-7b=5:3) and 1.42 g (9.342 mmole)of trimethyl hydroquinone, 250 μl of trifluoromethane sulfonic acid wasadded and the mixture was stirred at room temperature for 18 hours.

The reaction mixture was washed with water, dried and then concentratedunder a reduced pressure. The residue was dissolved in a mixed solution(50 ml) of acetanilide/water (=3/1 (V/V)), and 10.99 g (20.055 mmole) ofCAN was added, followed by stirring at room temperature for 30 minutes.The reaction mixture was diluted with water, then extracted with ether,and the extract was washed with water, dried and the solvent wasevaporated. The crude product was purified by silica gel chromatography(5% methanol/methylene chloride) to obtain 1.47 g of the title compound.

WORKING EXAMPLES 37-40

The following compounds were prepared from the compound 36 according toa method of Working Example 3.

    ______________________________________                                         ##STR66##                                                                    Compound                                                                      No.          R.sup.4                                                          ______________________________________                                        36           OH                                                               37                                                                                          ##STR67##                                                       38                                                                                          ##STR68##                                                       39                                                                                          ##STR69##                                                       40           OEt                                                              ______________________________________                                    

The physical properties of the compounds obtained above are listed inTable 2.

EVALUATION EXAMPLE 1 Hypobaric Hypoxia Activity

The hypobaric hypoxia activity was determined by using male ddY mice(body weight=22-30 g) as follows.

The test sample was suspended in a 1% gum arabic solution, and orallyadministered compulsorily at a ratio of 50 mg/kg. The test sampleadministered group was 7 mice per one group, and the control group(solvent solution administered group) 14 mice. One hour afteradministration of the test sample, mice were placed in a desiccator, thedesiccator was brought to a reduced pressure of 180 mm Hg by a vacuumpump and observation was made for 15 minutes. The time from initiationof the reduction of pressure to a stopping of aspiration was measured asthe survival time, and when alive after an elapse of 15 minutes, thesurvival time was assumed to be 15 minutes.

The ratio of the average survival time of the sample group to that ofthe control group was as shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Compound    Hypobaric Hypoxia Activity                                        No.         Sample (min)/Control (min)                                        ______________________________________                                         2          1.29**                                                             4          1.48*                                                              5          1.36**                                                             9          1.79*                                                              15a        1.41                                                               17a        1.50**                                                             18a        1.32                                                              20          1.36*                                                             23          1.33*                                                             29          1.25*                                                             30          1.18*                                                              33b        1.46                                                               35a        1.48                                                              ______________________________________                                         *Significant at a probability level of 5%                                     **Significant at a probability level of 1%                               

                                      TABLE 1                                     __________________________________________________________________________                                          IR                                      Compound                        Property                                                                            spectrum                                                                           NMR spectrum   Mass                No.   Structure                 (m.p.)                                                                              (ν cm.sup.-1)                                                                   (δ ppm)  spectrum            __________________________________________________________________________    R-1                                                                                  ##STR70##                Colorless crystalline                                                               1710 1682                                                                          1.85-2.10 (1H, m), 2.15-2.35                                                  (1H, m), 2.35-2.60 (1H, m),                                                   2.85-3.25 (4H, m), 7.15-7.40                                                  (2H, m), 7.48 (1H, t), 8.03                                                   (1H, d)                            R-2                                                                                  ##STR71##                Colorless crystalline                                                               1706 1678                                                                          1.70-2.05 (2H, m), 2.10-2.40                                                  (2H, m), 2.40-2.70 (3H, m),                                                   2.90-3.10 (2H, m), 7.10-7.40                                                  (2H, m), 7.46 (1H, t), 8.01                                                   (1H, d)                            R-3                                                                                  ##STR72##                Colorless crystalline 59-61°                                                 1708 1679 (CHCl.sub.3)                                                             1.40-2.10 (5H, m), 2.10-2.60                                                  (4H, m), 2.85-3.10 (2H, m),                                                   7.05-7.55 (4H, m), 8.02 (1H,                                                  d)                                 R-4                                                                                  ##STR73##                Colorless oily                                                                      1728 1683                                                                          1.25 (3H, t), 2.70-3.05 (2H,                                                  m), 3.05-3.35 (3H, m), 4.17                                                   (2H, q), 7.20-7.40 (2H, m),                                                   7.50 (1H, t), 8.03 (1H, d)         R-5                                                                                  ##STR74##                Colorless crystalline 77-78°                                                 1732 1646                                                                          1.28 (3H, t), 3.48 (2H, s),                                                   4.19 (2H, q), 7.30-7.55 (2H,                                                  m), 7.60-7.75 (1H, m), 7.95                                                   (1H, s), 8.15-8.30 (1H, m)         R-6                                                                                  ##STR75##                Colorless crystalline 64-65°                                                 1722 1640                                                                          1.22 (3H, t), 2.55-2.85 (4H,                                                  m), 4.12 (2H, q), 7.30-7.50                                                   (2H, m), 7.55-7.75 (1H, m),                                                   7.90 (1H, s), 8.15-8.30 (1H,                                                  m)                                 R-7a                                                                                 ##STR76##                134-136° C.                                                                  1782 1.65-1.95 (1H, m), 2.10-2.55                                                  (3H, m), 2.55-2.85 (1H, m),                                                   2.85-3.15 (2H, m), 4.97 (1H,                                                  d, J=10.4 Hz), 7.0-7.5 (4H, m)     R-7b                                                                                 ##STR77##                Colorless crystalline 102-103°                                               1766 1.50-1.75 (1H, m), 1.80-2.00                                                  (1H, m), 2.30-2.50 (1H, m),                                                   2.60-3.00 (4H, m), 5.42 (1H,                                                  d, J=6.1 Hz), 7.05-7.55 (4H,                                                  m)                                 R-8b                                                                                 ##STR78##                Colorless crystalline 85-86°                                                 1770 (CHCl.sub.3)                                                                  1.37 (3H, d), 1.65-1.90 (1H,                                                  m), 1.90-2.10 (1H, m),                                                        2.35-2.60 (2H, m), 2.60-2.95                                                  (2H, m), 5.52 (1H, d),                                                        7.00-7.55 (4H,                                                                               202 (M.sup.+)                                                                 129 (100)           R-8a                                                                                 ##STR79##                Colorless crystalline 110-112°                                               1778 (CHCl.sub.3)                                                                  1.25 (3H, d), 1.70-1.95 (1H,                                                  m), 1.95-2.15 (1H, m),                                                        2.25-2.45 (1H, m), 2.70-2.90                                                  (1H, m), 2.90-3.10 (2H, m),                                                   5.13 (1H, d), 7.05-7.50 (5H,                                                  m)             202 (M.sup.+)                                                                 91 (100)            R-9a                                                                                 ##STR80##                144-146° C.                                                                  1726 1.45-1.80 (2H, m), 1.80-2.20                                                  (3H, m), 2.55-3.10 (4H, m),                                                   5.10 (1H, d, J=10.4 Hz),                                                      7.00-7.30 (3H, m), 7.50-7.70                                                  (1H, m)                            R-9b                                                                                 ##STR81##                75-76° C.                                                                    1728 1.60-2.00 (3H, m), 2.10-2.40                                                  (2H, m), 2.40-2.70 (2H, m),                                                   2.70-3.00 (2H, m), 5.32 (1H,                                                  d, J=5.2 Hz), 7.00-7.55 (4H,                                                  m)                                 R-10(1)                                                                              ##STR82##                Colorless oily                                                                      1724 1638 (CHCl.sub.3)                                                             1.20-1.55 (2H, m), 1.55-1.90                                                  (4H, m), 1.90-2.20 (1H, m),                                                   2.04 and 2.10 (3H, each s)-                                                   2.20-2.45 (2H, m), 2.50-2.70                                                  (4H, m), 2.70-3.00 (2H, m),                                                   3.60-4.00 (4H, m), 5.79 and                                                   6.08 (1H, d and s-like)                                                       7.00-7.40 (4H,                                                                               361 (M.sup.+)                                                                 43 (100)            R-10(2)                                                                              ##STR83##                Colorless oily                                                                      1728 1636 (CHCl.sub.3)                                                             1.20-1.55 (2H, m), 1.55-1.90                                                  (4H, m), 1.90-2.20 (1H, m),                                                   2.04 and 2.10 (3H, each s),                                                   2.20-2.40 (2H, m), 2.70-3.00                                                  (2H, m), 3.35-3.75 (8H, m),                                                   5.78, 6.07 (1H, each d)                                                       7.05-7.40 (4H,                                                                               345 (M.sup.+)                                                                 129 (100)           R-10(3)                                                                              ##STR84##                Colorless oily                                                                      1733 1630 (CHCl.sub.3)                                                             1.20-1.90 (9H, m), 1.90-2.20                                                  (1H, m), 2.03 and 2.09 (3H,                                                   each s), 2.20-2.40 (2H, m),                                                   2.70-3.00 (2H, m), 3.20-3.65                                                  (4H, m), 5.79 and 6.08 (1H, d                                                 and s-like) 7.05-7.40 (4H,                                                                   343 (M.sup.+)                                                                 84 (100)            R-11                                                                                 ##STR85##                Colorless powder (49-50° C.)                                                 1768 2.20 (1H, d), 2.60-2.80 (1H,                                                  m), 2.90-3.30 (3H, m), 5.29                                                   (1H, d), 7.00-7.40  (4H, m)        R-12a                                                                                ##STR86##                Colorless powder 118-119° C.                                                 1788 2.35-2.85 (3H, m), 4.29 (1H,                                                  t), 4.60 (1H, d, d), 5.06 (1H,                                                d), 6.70-7.05 (2H, m),                                                        7.05-7.35 (2H, m)                  R-12b                                                                                ##STR87##                Colorless powder 101-102° C.                                                 1770 2.44 (1H, d, d), 2.86 (1H, d,                                                 d), 2.90-3.10 (1H, m), 3.83                                                   (1H, d, d), 4.21 (1H, d, d),                                                  5.49 (1H, d), 6.92 (1H, d),                                                   7.02 (1H, t), 7.15-7.50 (2H,                                                  m)                                 R-13a                                                                                ##STR88##                Colorless powder 139-142° C.                                                 1738 1.50-1.75 (1H, m), 1.95-2.40                                                  (2H, m), 2.60-2.95 (2H, m),                                                   3.94 (1H, t), 4.37 (1H, d, d),                                                .18 (1H, d), 6.84 (1H, d),                                                    6.98 (1H, t), 7.10-7.35 (1H,                                                  m), 7.40 (1H, d)                   R-13b                                                                                ##STR89##                Colorless powder 106-107° C.                                                 1740 1.45-1.70 (1H, m), 2.15-2.40                                                  (1H, m), 2.40-2.75 (2H, m),                                                   3.97 (1H, t), 4.12 (1H, d, d),                                                .33 (1H, d), 6.87 (1H, d),                                                    6.97 (1H, t), 7.05-7.45 (2H,                                                  m)                                 R-14                                                                                 ##STR90##                Oily  1780 2.46 (1H, d), 4.50-4.65 (1H,                                                  m), 4.80-4.95 (1H, m),                                                        5.30-5.40 (1H, m), 6.80-7.00                                                  (2H, m), 7.05-7.40 (2H, m)         R-15a                                                                                ##STR91##                Colorless crystalline 99-100°                                                1787 2.35-2.65 (2H, m), 2.70-2.95                                                  (1H, m), 3.12 (1H, t), 3.28                                                   (1H, d, d), 4.94 (1H, d,                                                      J=9.87 Hz), 7.05-7.30 (3H, m),                                                .42 (1H, d)                        R-15b                                                                                ##STR92##                Colorless crystalline 112-113°                                               1777 2.50-3.05 (4H, m), 3.05-3.25                                                  (1H, m), 5.49 (1H, d, J= 6.6                                                  Hz), 7.05-7.35 (3H, m), 7.47                                                  (1H, d)                            __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Compound      IR                                                              No.   Property                                                                              spectrum                                                                           NMR spectrum      Mass                                     (Example)                                                                           (m.p.)  (ν cm.sup.-1)                                                                   (δ ppm) (Temp. 60° C.)                                                             spectrum                                 __________________________________________________________________________     1    Hygroscopic                                                                           3000 1.50-1.75(1H, m), 1.88                                                                          370                                            powder  1704 (3H, s), 2.00-2.20(1H, m),                                                                      (M.sup.+, 100)                                         1647 2.20-2.45(2H, m), 2.45-2.70                                                   (1H, m), 2.75-2.95(1H, m),                                                    2.95-3.15(1H, m), 3.94                                                        (3H, s), 4.00(3H, s),                                                         4.15-4.40(1H, m), 6.71                                                        (1H, d), 6.90-7.15(3H, m)                                   2    Oily    3000 1.30-1.60(2H, m), 1.60-1.90                                                                     384                                                    1708 (1H, m), 1.85(3H, s),                                                                           (M.sup.+, 100)                                         1648 1.90-2.20(2H, m), 2.20-2.65                                                   (2H, m), 2.70-3.10(2H, m),                                                    3.93(3H, s), 4.00(3H, s),                                                     4.10-4.35(1H, m), 6.71                                                        (1H, d), 6.90-7.20(3H, m)                                   3    156-157° C.                                                                    1642 1.40-1.65(1H, m), 1.98                                                                          455 (M.sup.+)                                               (3H, s), 2.00-2.15(1H, m),                                                                      310 (100)                                                   2.15-2.35(2H, m), 2.40-2.75                                                   (5H, m), 2.75-2.90(1H, m),                                                    2.90-3.15(1H, m), 3.50-3.90                                                   (4H, m), 3.99(3H, s), 4.00                                                    (3H, s), 4.32(1H, d,                                                          J=9.5 Hz), 6.71(1H, d),                                                       6.90-7.15(3H, m)                                            4    150-151° C.                                                                    1640 1.45-1.65(1H, m), 439 (M.sup.+)                                               1.82(3H, s), 2.00-2.15                                                                          310 (100)                                                   (1H, m), 2.15-2.30(2H, m),                                                    2.55-2.75(1H, m), 2.75-2.90                                                   (1H, m), 2.90-3.15(1H, m),                                                    3.25-3.70(8H, m), 3.98                                                        (6H, s), 4.33(1H, d,                                                          J=8.7Hz), 6.70(1H, d),                                                        6.90-7.15(3H, m)                                            5    Oily    1643 1.40-1.65(1H, m), 1.82                                                                          452 (M.sup.+)                                               (3H, brs), 2.00-2.15(1H, m),                                                                     98 (100)                                                   2.15-2.40(6H, m), 2.27                                                        (3H, s), 2.50-2.75(1H, m),                                                    2.75-2.90(1H, m), 2.90-3.15                                                   (1H, m), 3.25-3.70(4H, m),                                                    3.99(6H, s), 4.20-4.40                                                        (1H, m), 6.70(1H, d),                                                         6.90-7.15(3H, m)                                            6    Oily    1642 1.30-1.70(7H, m), 1.82                                                                          437 (M.sup.+)                                               (3H, brs), 2.00-2.15(1H, m),                                                                    310 (100)                                                   2.15-2.40(2H, m), 2.50-2.75                                                   (1H, m), 2.75-3.15(2H, m),                                                    3.15-3.60(4H, m), 3.99                                                        (6H, s), 4.20-4.40(1H, m),                                                    6.71(1H, d), 6.90-7.15(3H, m)                               7    Oily    1722 1.20(3H, t), 1.50-1.70                                                                          398                                                    1648 (1H, m), 1.88(3H, brs),                                                                         (M.sup.+, 100)                                              2.00-2.15(1H, m), 2.15-2.35                                                   (2H, m), 2.45-2.70(1H, m),                                                    2.70-2.90(1H, m), 2.90-3.15                                                   (1H, m), 3.97(3H, s), 3.99                                                    (3H, s), 4.07(2H, q),                                                         4.15-4.35(1H, m), 6.69                                                        (1H, d), 6.90-7.15(3H, m)                                   8    Hygroscopic                                                                           1642 1.30-1.60(2H, m), 1.65-1.95                                                                     469 (M.sup.+)                                  powder       (1H, m), 1.83(3H, s),                                                                           310 (100)                                                   1.95-2.70(8H, m), 2.70-3.10                                                   (2H, m), 3.50-4.00(4H, m),                                                    3.93(3H, s), 4.00(3H, s),                                                     4.10-4.35(1H, m), 6.70                                                        (1H, d), 6.85-7.20(3H, m)                                   9    117-118°  C.                                                                   1646 1.30-1.60(2H, m), 1.65-1.95                                                                     453 (M.sup.+)                                               (1H, m), 1.87(3H, s),                                                                            88 (100)                                                   2.00-2.55(4H, m), 2.75-3.10                                                   (2H, m), 3.30-3.70(8H, m),                                                    3.94(3H, s), 4.01(3H, s),                                                     4.10-4.35(1H, m), 6.73                                                        (1H, d), 6.90-7.15(3H, m)                                  10    Reddish 1645 1.21(3H, t) 1.30-1.60(2H, m)                                                                    412 (M.sup.+, 100)                             yellow  1730 1.85(3H, s)1.60-2.20(3H, m)                                      oily         2.20-2.50(2H, m)2.75-3.10(2H, m)                                              3.95(3H, s)4.01(3H, s)4.08(2H, q)                                             4.00-4.35(1H, br, m)6.71(1H, d)                                               6.90-7.20(3H, m)                                           11    Oily    1648 1.10-1.65(4H, m), 1.65-2.35                                                                     483 (Mt.sup.+)                                         (CHCl.sub.3)                                                                       (5H, m), 1.83(3H, s),                                                                           184 (100)                                                   2.45-2.70(4H, m), 2.70-3.10                                                   (2H, m), 3.60-3.95(4H, m),                                                    3.96(3H, s), 4.01(3H, s),                                                     4.00-4.35(1H, m), 6.69                                                        (1H, d), 6.90-7.15(3H, m),                                                    (55° C.)                                            12    Oily    1644 1.10-1.65(4H, m), 1.65-1.95                                                                     467 (Mt.sup.+)                                         (CHCl.sub.3)                                                                       (1H, m), 1.83(3H, s),                                                                           184 (100)                                                   1.95-2.30(4H, m), 2.75-3.05                                                   (2H, m), 3.30-3.75(8H, m),                                                    3.95(3H, s), 4.01(3H, s),                                                     4.10-4.35(1H, m), 6.68                                                        (1H, d), 6.90-7.15(3H, m)                                                     (55° C.)                                            13    Oily    1645 1.10-2.30(18H, m), 2.70-3.10                                                                    465 (Mt.sup.+)                                         (CHCl.sub.3)                                                                       (2H, m), 3.25-3.55(4H, m),                                                                      127 (100)                                                   3.95(3H, s), 4.01(3H, s),                                                     4.05-4.35(1H, m), 6.68                                                        (1H, d), 6.90-7.15(3H, m)                                   14a  Yellow powder                                                                         1710 1.79(3H, brs), 1.85-2.15                                         (76-78° C.)                                                                    1652 (1H, m), 2.20-2.35(1H, m),                                                    2.75-2.95(1H, m), 3.11                                                        (2H, d), 3.93(3H, s), 4.00                                                    (3H, s), 4.45-4.75(1H, m),                                                    6.77(1H, d), 6.95-7.15                                                        (3H, m), (60° C.*)                                   14b  Yellow crystal-                                                                       1706 1.93(3H, s), 2.00-2.20                                           line    1652 (1H, m), 2.20-2.40(1H, m),                                       (156-159° C.)                                                                       3.00-3.25(3H, m), 3.91                                                        (3H, s), 4.00(3H, s),                                                         4.45-4.65(1H, m), 6.74                                                        (1H, d), 6.90-7.25(3H, m)                                   15a  Yellow powder                                                                         1644 1.68(3H, brs), 1.85-2.20                                         (87-89° C.)                                                                         (2H, m), 2.50-2.75(4H, m),                                                    2.75-2.90(1H, m), 2.90-3.10                                                   (1H, m), 3.10-3.30(1H, m),                                                    3.70-4.00(4H, m), 3.98                                                        (3H, s), 4.00(3H, s),                                                         4.55-4.85(1H, m), 6.80                                                        (1H, d), 6.95-7.20(3H, m),                                                    (60° C.*)                                            15b  Yellow powder                                                                         1644 1.97(3H, s), 1.85-2.05                                           (58-60° C.)                                                                         (1H, m), 2.15-2.35(1H, m),                                                    2.50-2.70(4H, m), 3.01                                                        (2H, d), 3.15-3.35(1H, m),                                                    3.65-4.00(4H, m), 3.93                                                        (3H, s), 4.02(3H, s), 4.50                                                    (1H, t), 6.77(1H, d),                                                         6.95-7.20(3H, m)                                            16a  Yellow powder                                                                         1644 1.68(3H, s), 1.85-2.15                                           (80-82° C.)                                                                         (2H, m), 2.75-2.90(1H, m),                                                    2.90-3.10(1H, m), 3.10-3.35                                                   (1H, m), 3.45-3.80(8H, m),                                                    3.98(3H, s), 3.99(3H, s),                                                     4.60-4.85(1H, m), 6.80                                                        (1H, d), 6.95-7.20(3H, m),                                                    (60° C.*)                                            17a  Yellow crystal-                                                                       1644 1.07 (3H, brs), 1.85-2.20                                        line         (2H, m), 2.31(3H, s),                                            (69-71° C.)                                                                         2.20-2.60(4H, m), 2.75-2.90                                                   (1H, m), 2.90-3.10(1H, m),                                                    3.10-3.30(1H, m), 3.45-3.75                                                   (4H, m), 3.98(3H, s), 3.99                                                    (3H, s), 4.55-4.90(1H, m),                                                    6.80(1H, d), 6.90-7.20                                                        (3H, m), (60° C.*)                                   18a  Oily    1728 1.78(3H, s), 1.80-2.10                                                   1650 (1H, m), 2.15-2.35(1H, m),                                                    2.75-2.95(1H, m), 3.00-3.20                                                   (2H, m), 3.95(3H, s), 4.00                                                    (3H, s), 4.50-4.75(1H, m),                                                    5.18(2H, s), 6.77(1H, d),                                                     6.95-7.15(3H, m), 7.15-7.45                                                   (5H, m)                                                     18b  Oily    1724 1.83(3H, s), 2.00-2.20                                                   1646 (1H, m), 2.25-2.45(1H, m),                                                    3.05-3.30(3H, m), 3.93                                                        (3H, s), 4.00(3H, s),                                                         4.40-4.55(1H, m), 5.12                                                        (2H, s), 6.73(1H, d),                                                         6.95-7.40(8H, m)                                           19    Yellow crystal-                                                                       3000 1.81(3H, brs), 2.15-2.40                                                                        372 (M.sup.+)                                  line    1708 (2H, m), 2.70-2.95(1H, m),                                       137-139° C.                                                                    1647 3.85(1H, t), 3.97(3H, s),                                                     4.00(3H, s), 4.30-4.55                                                        (2H, m), 6.60-6.90(3H, m),                                                    7.08(1H, t), (Temp. 55° C.)                         20    Yellow crystal-                                                                       3000 1.35-1.60(1H, m), 1.60-1.90                                                                     386 (M.sup.+  100)                             line    1708 (4H, m), 2.15-2.55(3H, m),                                       159-161° C.                                                                    1648 3.76(1H, t), 3.97(3H, s),                                                     4.01(3H, s), 4.15-4.50                                                        (2H, m), 6.60-6.90(3H, m),                                                    6.95-7.15(1H, m),                                                             (Temp. 55° C.)                                      21    Yellow crystal-                                                                       1646 1.76(3H, s), 2.10-2.35                                                                          457 (M.sup.+  100)                             line         (2H, m), 2.40-2.65(4H, m),                                       187-189° C.                                                                         2.80-3.00(1H, m), 3.55-3.95                                                   (5H, m), 4.02(6H, s),                                                         4.25-4.55(2H, m), 6.65-6.90                                                   (3H, m), 7.08(1H, t),                                                         (Temp. 55° C.)                                      22    Yellow crystal-                                                                       1644 1.70(3H, brs), 2.10-2.35                                                                        441 (M.sup.+)                                  line         (2H, m), 2.75-3.00(1H, m),                                                                      258 (100)                                      186-187° C.                                                                         3.30-3.70(8H, m), 3.82                                                        (1H, t), 4.02(6H, s), 4.40                                                    (1H, d, d), 4.25-4.60(1H, m),                                                 6.65-6.90(3H, m), 7.10                                                        (1H, t)                                                    23    Yellow crystal-                                                                       1641 1.77(3H, brs), 2.27(3H, s),                                                                     454 (M.sup.+  100)                             line         2.10-2.40(6H, m), 2.80-3.00                                      147-149° C.                                                                         (1H, m), 3.25-3.65(4H, m),                                                    3.82(1H, t), 4.00(6H, s),                                                     4.30-4.50(2H, m), 6.65-6.90                                                   (3H, m), 7.00-7.15(1H, m)                                  24    Yellow powder                                                                         1644 1.40-1.65(1H, m), 1.65-1.95                                                                     471 (M.sup.+)                                               (4H, m), 2.15-2.50(3H, m),                                                                      440 (100)                                                   3.50-3.65(4H, m), 3.60-3.90                                                   (5H, m), 3.97(3H, s), 4.01                                                    (3H, s), 4.31(1H, d, d),                                                      4.15-4.45(1H, m), 6.65-6.90                                                   (3H, m), 7.06(1H, t),                                                         (Temp. 55° C.)                                      25    Yellow powder                                                                         1646 1.30-1.65(1H, m), 1.65-1.95                                                                     455 (M.sup.+)                                               (4H, m), 2.10-2.50(3H, m),                                                                      424 (100)                                                   3.25-3.70(8H, m), 3.79                                                        (1H, t), 3.97(3H, s), 4.01                                                    (3H, s), 4.20-4.45(2H, m),                                                    6.60-6.90(3H, m), 6.95-7.15                                                   (1H, m)                                                    26    Oily    3000 1.86(3H, s), 2.30-2.60                                                   1728 (2H, m), 3.97(3H, s), 4.01                                               1650 (3H, s), 4.35-4.60(1H, m),                                                    4.90-5.10(1H, m), 6.73                                                        (1H, d), 6.84(1H, t), 6.97                                                    (1H, d), 7.14(1H, t)                                       27    Yellow crystal-                                                                       1650 2.04(3H, s), 2.10-2.50                                           line         (2H, m), 2.50-3.00(4H, m),                                       (144-146° C.)                                                                       3.40-4.00(4H, m), 3.92                                                        (3H, s), 4.01(3H, s),                                                         4.70-4.85(1H, m), 5.00-5.15                                                   (1H, m), 6.70-6.95(3H, m),                                                    7.10(1H, t)                                                28    Orange yellow                                                                         1649 2.03(3H, s), 2.15-2.55                                           powder       (2H, m), 3.35-3.90(8H, m),                                       (79-81° C.)                                                                         3.93(3H, s), 4.00(3H, s),                                                     4.78(1H, t-like), 5.08                                                        (1H, t-like), 6.65-6.95                                                       (3H, m), 7.09(1H, t)                                       29    Yellow crystal-                                                                       3000 1.82(3H, s), 2.38(2H, d),                                                                       388 (M.sup.+  100)                             line    1704 2.70-3.10(3H, m), 4.00                                           67-69° C.                                                                      1646 (3H, s), 4.02(3H, s), 4.47                                                    (1H, d), 6.72(1H, d), 6.93                                                    (1H, t), 7.04(1H, t), 7.13                                                    (1H, d)                                                    30    Yellow crystal-                                                                       1647 1.78(3H, s), 2.28(1H, d, d),                                                                    473 (M.sup.+)                                  line         2.41(1H, d, d), 2.40-2.70                                                                       328 (100)                                      188-190° C.                                                                         (4H, m), 2.75-3.10(3H, m),                                                    3.55-3.95(4H, m), 4.01                                                        (3H, s), 4.02(3H, s), 4.47                                                    (1H, d), 6.73(1H, d), 6.93                                                    (1H, t), 7.04(1H, t) 7.13                                                     (1H, d)                                                    31    Yellow crystal-                                                                       1652 1.78(3H, s), 2.28(1H, d, d),                                                                    457 (M.sup.+)                                  line         2.41(1H, d, d), 2.75-3.10                                                                       328 (100)                                      182-183° C.                                                                         (3H, m), 3.25-3.75(8H, m),                                                    4.01(3H, s), 4.02(3H, s),                                                     4.47(1H, d), 6.73(1H, d),                                                     6.93(1H, t), 7.04(1H, t),                                                     7.13(1H, d)                                                32    Yellow crystal-                                                                       1648 1.76(3H, s), 2.30-2.50                                                                          470 (M.sup.+)                                  line         (2H, m), 2.68(3H, s),                                                                            70 (100)                                      167-169° C.                                                                         2.55-3.20(7H, m), 3.60-4.20                                                   (4H, m), 4.02(3H, s), 4.03                                                    (3H, s), 4.47(1H, d), 6.75                                                    (1H, d), 6.96(1H, t), 7.07                                                    (1H, t), 7.15(1H, d)                                        33a  Yellow crystals                                                                       2943 1.15(3H, d), 1.55-1.80                                                                          384 (M.sup.+)                                  154-155° C.                                                                    1703 (1H, m), 1.97(3H, brs),                                                                         323 (100)                                              1650 1.85-2.10(1H, m), 2.40-2.65                                              1607 (2H, m), 2.75-3.15(2H, m),                                               (KBr)                                                                              3.91(3H, s), 3.97(3H, s),                                                     4.53(1H, d-like), 6.71                                                        (1H, d), 6.85-7.15(3H, m),                                                    (Temp. 55° C.)                                       33b  Yellow crystals                                                                       2930 1.19(3H, d), 1.45-1.70                                                                          384 (M.sup.+)                                  157.5-159° C.                                                                  1694 (1H, m), 1.85(3H, s),                                                                           323 (100)                                              1657 1.80-2.05(1H, m), 2.20-2.45                                              1649 (1H, m), 2.55-2.75(1H, m),                                               1609 2.75-3.10(2H, m), 3.96                                                   (KBr)                                                                              (3H, s), 4.00(3H, s),                                                         4.25-4.60(1H, m), 6.70                                                        (1H, d), 6.90-7.15(3H m)                                                      (Temp. 55° C.)                                       34a  Yellow crystals                                                                       1650 1.11(3H, d), 1.74(3H, s)                                                                        469 (M.sup.+)                                  165-166.5° C.                                                                  1632 1.75-2.05(2H, m), 2.30-2.75                                                                     159 (100)                                              1613 (6H, m), 2.75-3.10(2H, m),                                               (KBr)                                                                              3.25-3.85(4H, m), 3.98                                                        (3H, s), 4.03(3H, s), 4.58                                                    (1H, d), 6.90(1H, d),                                                         6.90-7.15(3H, m),                                                             (Temp. 55° C.)                                       34b  Yellow crystals                                                                       1651 1.13(3H, d), 1.35-165(1H, m)                                                                    469 (M.sup.+)                                  108-109° C.                                                                    1635 1.88(3H, s), 2.05-2.25                                                                          159 (100)                                              (KBr)                                                                              (1H, m), 2.35-2.65(6H, m),                                                    2.75-3.10(2H, m), 3.35-4.10                                                   (4H, m), 3.99(6H, s),                                                         4.20-4.40(1H, m), 6.68                                                        (1H, d), 6.90-7.15(3H, m),                                                    (Temp. 55° C.)                                       35a  Yellow crystals                                                                       1650 1.12(3H, d), 1.78(3H, s),                                                                       453 (M.sup.+)                                  167-168.5° C.                                                                  1632 1.80-2.05(2H, m), 2.30-2.50                                                                     143 (100)                                              (KBr)                                                                              (1H, m), 2.55-2.75(1H, m),                                                    2.75-3.10(2H, m), 3.15-3.75                                                   (8H, m), 3.98(3H, s), 4.04                                                    (3H, s), 4.58(1H, d), 6.71                                                    (1H, d), 6.90-7.15(3H, m),                                                    (Temp. 55° C.)                                       35b  Yellow crystals                                                                       1650 1.13(3H, d), 1.40-1.65                                                                          453 (M.sup.+)                                  134-136° C.                                                                    1631 (1H, m), 1.89(3H, s),                                                                           143 (100)                                              (KBr)                                                                              2.05-2.25(1H, m), 2.40-2.65                                                   (2H, m), 2.80-3.10(2H, m),                                                    3.15-3.70(8H, m), 3.99                                                        (6H, s), 4.20-4.40(1H, m),                                                    6.69(1H, d), 6.90-7.15                                                        (3H, m), (Temp. 55° C.)                             36    Yellowish red                                                                         1645 1.40-2.45(13H, m), 2.45-3.20                                                                    338 (M.sup.+  100)                             hygroscopic                                                                           1710 (3H, m), 4.10-4.40(1H, br, m),                                   powder  (CHCl.sub.3)                                                                       6.60-6.90(1H, m), 6.90-7.35                                      63-67° C.                                                                           (3H, m)                                                    37    Yellowish red                                                                         1645 1.40-3.20(20H, m), 3.40-9.00                                                                    423 (M.sup.+)                                  powder  (KBr)                                                                              (4H, m), 4.15-4.50(1H, m),                                                                      278 (100)                                      147-152° C.                                                                         6.60-6.85(1H, m), 6.90-7.20                                                   (3H, m)                                                    38    Yellow crystals                                                                       1642 1.35-1.65(1H, m), 1.70-2.35                                                                     407 (M.sup.+)                                  179-182° C.                                                                    (KBr)                                                                              (12H, m), 2.35-3.20(3H, m),                                                                     278 (100)                                                   3.2-3.8(8H, m), 4.2-4.45                                                      (1H, m), 6.60-6.80(1H, m),                                                    6.90-7.20(3H, m)                                           39    Yellow crystal-                                                                       1642 1.40-2.50(20H, m), 2.50-3.20                                                                    420 (M.sup.+)                                  line (hydro-                                                                          (CHCl.sub.3)                                                                       (3H, m), 3.20-3.7(4H, m),                                                                       278 (100)                                      chloride)    4.3- 4.7(1H, m), 6.60-7.20                                       147-153° C.                                                                         (4H, m)                                                    40    Yellow oily                                                                           1648 1.20(3H, t), 1.50-2.40                                                                          366 (M.sup.+)                                          1728 (13H, m), 2.45-3.15(3H, m),                                                                     278 (100)                                              (CHCl.sub.3)                                                                       4.04(2H, q), 4.05-4.40                                                        (1H, m), 6.60-6.90(1H, m),                                                    6.90-7.20(3H, m)                                           __________________________________________________________________________

We claim:
 1. A compound having the formula (I): ##STR93## wherein A is--O--, or --S--; R¹ is CH₃ or OCH₃ ; R² is --COR⁴ wherein R⁴ is amorpholino group, thiomorpholino group, piperidino group or N-methylpiperazinyl group; R³ is H or a lower alkyl; and n is 0 or an integer of1 to 6 and a salt thereof.
 2. A compound as claimed in claim 1,represented by the formula (IV): ##STR94## wherein p is 1 or 2; R⁴ is amorpholino group, thiomorpholino group, piperidino group orN-methylpiperazinyl group.
 3. A compound as claimed in claim 1,represented by the formula (V): ##STR95## wherein R⁴ is a morpholinogroup, thiomorpholino group, piperidino group or N-methylpiperazinylgroup.
 4. A compound as claimed in claim 1, represented by the formula(VI): ##STR96## wherein R⁴ is a morpholino group, thiomorpholino group,piperidino group or N-methylpiperazinyl group.
 5. A pharmaceuticalcomposition useful as an improver of cerebral insufficiency caused bycerebral ischemia comprising an effective amount of a compound of theformula (I) to improve a cerebral insufficiency caused by cerebralischemia: ##STR97## wherein A is --O--, or --S--; R¹ CH₃ or OCH₃ ; R² is--COR⁴ wherein R⁴ is a morpholino group, thiomorpholino group,piperidino group or N-methyl piperazinyl group; R³ is H or a loweralkyl; and n is 0 or an integer of 1 to 6 and a pharmaceuticallyacceptable carrier therefor.
 6. The pharmaceutical composition asclaimed in claim 5 represented by formula (IV): ##STR98## wherein p is 1or 2; R⁴ is a morpholino group, thiomorpholino group, piperidino groupor N-methylpiperazinyl group.
 7. The pharmaceutical composition asclaimed in claim 5 represented by the formula (V): ##STR99## wherein R⁴is a morpholino group, thiomorpholino group, piperidino group orN-methylpiperazinyl group.
 8. The pharmaceutical composition as claimedin claim 5 represented by the formula (VI): ##STR100## wherein R⁴ is amorpholino group, thiomorpholino group, piperidino group orN-methylpiperazinyl group.
 9. A method for improving cerebralinsufficiency caused by cerebral ischemia, comprising administering aneffective amount of a compound of the formula I to improve cerebralinsuficiency caused by cerebral ischemia: ##STR101## wherein A is --O--or --S--; R¹ is CH₃ or OCH₃ ; R² is --COR⁴ wherein R⁴ is a morpholinogroup, thiomorpholino group, piperidino group or N-methyl piperazinylgroup; R³ is H or a lower alkyl; and n is 0 or an integer of 1 to 6 anda salt thereof, to a patient in need of such treatment.
 10. The methodas claimed in claim 9 for improving cerebral insufficiency caused bycerebral ischemia comprising administering an effective amount of acompound of the formula (IV) to improve cerebral insufficiency caused bycerebral ischemia: ##STR102## wherein p is 1 or 2; R⁴ is a morpholinogroup, thiomorpholino group, piperidino group or N-methylpiperazinylgroup, to a patient in need of such treatment.
 11. The method as claimedin claim 9 for improving cerebral insufficiency caused by cerebralischemia comprising administering an effective amount of a compound ofthe formula (V) to improve cerebral insufficiency caused by cerebralischemia: ##STR103## wherein R⁴ is a morpholino group, thiomorpholinogroup, piperidino group or N-methylpiperazinyl group, to a patient inneed of such treatment.
 12. The method as claimed in claim 9 forimproving cerebral insufficiency caused by cerebral ischemia comprisingadministering an effective amount of a compound of the formula (VI) toimprove cerebral insufficiency caused by cerebral ischemia: ##STR104##wherein R⁴ is a morpholino group, thiomorpholino group, piperidino groupor N-methylpiperazinyl group, to a patient in need of such treatment.